Adolescence is a critical neurodevelopmental period associated with dramatic increases in rates of substance use. Identifying the pathways to substance use and its effects on child and adolescent development is critically important, as the effects of substance use during ongoing maturation likely have long-lasting effects on brain functioning and behavioral, health, and psychological outcomes. This Research Project Site application from the University of Wisconsin-Milwaukee, Mass General Hospital, and University of Texas at Dallas is in response to RFA-DA-15-015 as part of the ABCD-USA Consortium (4/13), to prospectively determine the neurodevelopmental and behavioral predictors and consequences of substance use on children and adolescents. A representative community sample of 1550 9-10 year olds enriched for high-risk characteristics will be recruited, contributing to the sample of 11,111 to be collected from 11 hubs across the ABCD-USA Consortium. All participants will undergo a comprehensive baseline assessment, including state-of-the-art brain imaging, comprehensive neuropsychological testing, bioassays, mobile monitoring and careful assessment of substance use, environment, psychopathological symptoms, and social functioning every 2 years. Interim annual interviews and quarterly web-based assessments will provide refined temporal resolution of behaviors, development, and life events with minimal participant burden. These Consortium-wide data obtained during the course of this project will elucidate: 1) the effects of substance use patterns on the adolescent brain; 2 the effects of substance use on behavioral and health outcomes; 3) the bidirectional relationship between psychopathology and substance use patterns; 4) the effects of individual genetic, behavioral, neurobiological, and environmental differences on risk profiles and substance use outcomes; and 5) the gateway interactions between use of different substances. Specific 4/13 Aims include: 1) To examine the impact of in-vivo endocannabinoid (eCB) (anandamide, 2AG, CB1R protein) tone on youth substance use, brain structure, white matter integrity, functional connectivity, cognition, psychopathology, and health outcomes (stress, sleep, adiposity, physical activity), if marijuana (MJ) predicts eCB tone, and whether eCB tone moderates MJ effects on neurocognition; 2) To determine the reciprocal predictive association between psychopathology and MJ use markers in youth; 3) To determine whether MJ use patterns predict changes in youth brain structure, white matter integrity, functional connectivity, cognitio, and health outcomes trajectories and to determine whether psychopathology and health factors moderate these MJ effects. This application will advance our understanding of the endogenous eCB system, prospectively determine the impact of psychopathology on MJ use patterns, and will determine whether specific MJ use patterns (age of onset, total exposure, THC:CBD, product types, routes of use) prospectively predict psychopathology, neurocognitive, and health trajectories in youth. Findings will significantly inform prevention campaigns, public health and MJ policy.